Regular articleA randomized controlled trial evaluating the efficacy and safety of intermittent 3-, 4-, and 5-day cycles of intravenous recombinant human Interleukin-2 combined with antiretroviral therapy (ART) versus ART alone in HIV-seropositive patients with 100–300 CD4+ t cells
Introduction
Although advances over the last 15 years in the treatment of human immunodeficiency virus (HIV) with ART or highly active antiretroviral therapy (HAART) have dramatically reduced mortality and morbidity, complete eradication of HIV remains elusive; thus, long-term therapeutic strategies must be developed [1]. Immune modulators used as adjuvants to antiretroviral therapy may accelerate the rate and improve the degree of immunologic recovery during HIV infection. Moreover, in light of emerging severe toxicity problems associated with chronic HAART usage, development of effective immunotherapies that are able to decrease exposure to HAART, facilitate immune reconstitution, and augment HIV-specific and/or opportunistic infection-specific immunity could offer valuable therapeutic options for HIV-infected patients. Interleukin-2 (IL-2) is a pleiotropic cytokine predominantly produced by activated CD4+ T cells. It plays an essential role in the development of both adaptive and innate immunity. IL-2 also plays a critical role in the regulation of T-cell homeostasis and is known to promote cell survival, growth, and differentiation of antigen-activated T cells into mature effector T cells.
Several controlled clinical trials have shown that administration of IL-2 can result in impressive and sustained increases in CD4+ T-cell counts in the majority of treated HIV-infected patients receiving ART [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. The expansion of the CD4+ T-cell pool after intermittent administration of IL-2 is polyclonal and represents the net effect of this T-cell growth factor on CD4+ T-cell proliferation and survival [12]. A series of studies in patients with CD4+ T-cell counts >200 or 350/mm3 have determined the optimal dose and interval between IL-2 cycles [9], [10], [11], [13]. The purpose of the present study was to examine the effect of length of CIV IL-2 therapy on CD4+ T-cell response in patients with lower CD4+ T-cell counts (between 100 and 300/mm3). To assess the effects of duration of treatment on CD4+ T-cell count response, patients were randomized to ART alone or to treatment for 3, 4, or 5 days of CIV IL-2 therapy every 8 weeks in combination with ART. Because a total dose of 18 mIU/day was not well tolerated in the study by Kovacs et al. [2] and initial trials of both native and recombinant IL-2 were well tolerated with dosages up to 12 mIU/day, therapy was initiated in the current study at 12 mIU/day for all IL-2 treatment groups.
Section snippets
Study design
In this randomized, controlled trial, HIV-infected patients at least 18 years of age with CD4+ T-cell counts of 100–300/mm3 were eligible for enrollment if they had been on a stable ART regimen for at least 2 months prior to the study, had no acquired immunodeficiency syndrome (AIDS)-defining diagnoses other than Kaposi’s sarcoma or a single episode of Pneumocystis carinii pneumonia (PCP), and were in overall good health, with a Karnofsky performance status ≥70. The study was conducted in five
Patients
Eighty-one patients (78 males and 3 females) were enrolled in the trial between January and November 1994. Twenty-one patients were randomized to the 3-day CIV IL-2 group, 20 to the 4-day CIV IL-2 group, 19 to the 5-day CIV IL-2 group, and 21 to the control group. The baseline characteristics of the patients are summarized in Table 1. No imbalances were found in baseline demographic data between groups. The median CD4+ T-cell count at entry was approximately 200 cells/mm3 across all groups, and
Discussion
Data in the literature on the use of IL-2 in HIV-infected individuals with CD4+ T-cell counts of 100–300/mm3 are scarce. The potential of intermittent SC IL-2 to increase CD4+ T cell numbers in patients with CD4+ T cell count < 250 cells/microl has been demonstrated in two additional published studies [23], [24]. In contrast to those trials, the patients in the present study had poorer control of viral replication thus raising the possibility that IL-2 may be of value as part of a salvage
Acknowledgements
This study was supported by a Chiron Corporation study grant. We acknowledge the excellent work and dedication of the study coordinators Karen McKenzie, Judy Carden, Victoria Davey, Amy Carnicom, and Jan Kosmyna, Dr. Michael C Sneller for careful review and significant additional suggestions on the manuscript, William Capra for additional statistical analysis, and Melissa Hurley and Carol Bundgus for help with manuscript preparation.
References (34)
- et al.
ANRS 048 study group, Comparison of subcutaneous and intravenous interleukin-2 in asymptomatic HIV-1 infectiona randomised controlled trial
Lancet
(1999) - et al.
Immunotherapy of HIV-infected patients with intermittent interleukin-2effects of cycle frequency and cycle duration on degree of CD4(+) T-lymphocyte expansion
Clin. Immunol.
(2001) - et al.
Long-term effects of intermittent interleukin 2 therapy in patients with HIV infectioncharacterization of a novel subset of CD4+/CD25+ T cells
Blood
(2002) The impact of highly active antiretroviral therapy on HIV-specific immune function
AIDS
(2001)- et al.
Increases in CD4 T lymphocytes with intermittent courses of interleukin-2 in patients with human immunodeficiency virus infection—a preliminary study
N. Engl. J. Med.
(1995) - et al.
Controlled trial of interleukin-2-infusions in patients infected with the human immunodeficiency virus
N. Engl. J. Med.
(1996) - et al.
Subcutaneous administration of interleukin-2 in human immunodeficiency virus type 1-infected persons
J. Infect. Dis.
(1997) - et al.
A randomized trial of high- versus low-dose subcutaneous interleukin-2 outpatient therapy for early human immunodeficiency virus type 1 infection
J. Infect. Dis.
(1999) - et al.
Outpatient continuous intravenous interleukin-2 or subcutaneous, polyethylene glycol-modified interleukin-2 in human immunodeficiency virus-infected patientsa randomized, controlled, multicenter study. Australian IL-2 Study Group
J. Infect. Dis.
(1998) - et al.
Efficacy of low-dose intermittent subcutaneous interleukin (IL)-2 in antiviral drug-experienced human immunodeficiency virus-infected persons with detectable virus loada controlled study of 3 IL-2 regimens with antiviral drug therapy
J. Infect. Dis.
(2001)
Vanguard Study Group, A randomized, controlled, phase II trial comparing escalating doses of subcutaneous interleukin-2 plus antiretrovirals versus antiretrovirals alone in human immunodeficiency virus-infected patients with CD4+ cell counts ≥350/mm3
J. Infect. Dis.
for the Terry Beirn Community Programs for Clinical Research on AIDS, Randomized, Open-Label Study of the Impact of Two Doses of Subcutaneous Recombinant Interluekin-2 on Viral Burden in Patients With HIV-1 Infection and CD4+ T Cell Counts of >300/mm3CPCRA 059
JAIDS
Vanguard Study Group, A randomized, controlled 24-week study of intermittent subcutaneous interleukin-2 in HIV-1 infected patients in Thailand
AIDS
Immunopathogenesis of human immunodeficiency virusimplications for immune-based therapies
Clin. Infect. Dis.
MMWR Morb. Mortal. Wkly. Rep.
Application of branched DNA signal amplification to monitor human immunodeficiency virus type I burden in human plasma
J. Infect. Dis.
Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria
Inv. New Drugs.
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- 1
Currently at St. John Hospital and Wayne State University School of Medicine, Detroit, MI, USA.
- 2
Currently at Genentech Corporation, South San Francisco, CA, USA.